MiR-30a-5p and miR-153-3p regulate LPS-induced neuroinflammatory response and neuronal apoptosis by targeting NeuroD1.

Neurogenic differentiation 1 (NeuroD1) is an essential transcription factor for neuronal differentiation, maturation, and survival, and is associated with inflammation in lipopolysaccharide (LPS)- induced glial cells; however, the concrete mechanisms are still ambiguous. Therefore, we investigated whether NeuroD1-targeting miRNAs affect inflammation and neuronal apoptosis, as well as the underlying mechanism. First, we confirmed that miR-30a-5p and miR-153-3p, which target NeuroD1, reduced NeuroD1 expression in microglia and astrocytes.

Anti-inflammatory effects of N-cyclooctyl-5-methylthiazol-2-amine hydrobromide on lipopolysaccharide-induced inflammatory response through attenuation of NLRP3 activation in microglial cells.

Microglial activation is closely associated with neuroinflammatory pathologies. The nucleotide-binding and oligomerization domain-like receptor containing a pyrin domain 3 (NLRP3) inflammasomes are highly organized intracellular sensors of neuronal alarm signaling. NLRP3 inflammasomes activate nuclear factor kappa-B (NF-κB) and reactive oxygen species (ROS), which induce inflammatory responses.

S100A8 and S100A9 Promote Apoptosis of Chronic Eosinophilic Leukemia Cells.

S100A8 and S100A9 function as essential factors in inflammation and also exert antitumor or tumorigenic activity depending on the type of cancer. Chronic eosinophilic leukemia (CEL) is a rare hematological malignancy having elevated levels of eosinophils and characterized by the presence of the fusion gene. In this study, we examined the pro-apoptotic mechanisms of S100A8 and S100A9 in FIP1L1-PDGFRα+ eosinophilic cells and hypereosinophilic patient cells.

N-Adamantyl-4-methylthiazol-2-amine suppresses glutamate-induced autophagic cell death via PI3K/Akt/mTOR signaling pathways in cortical neurons.

We recently reported that N-adamantyl-4-methylthiazol-2-amine (KHG26693) attenuates glutamate-induced oxidative stress and inflammation in the brain. In this study, we investigated KHG 26693 as a therapeutic agent against glutamate-induced autophagic death of cortical neurons. Treatment with KHG26693 alone did not affect the viability of cultured cortical neurons but was protective against glutamate-induced cytotoxicity in a concentration-dependent manner.

KHG21834 attenuates glutamate-induced mitochondrial damage, apoptosis, and NLRP3 inflammasome activation in SH-SY5Y human neuroblastoma cells.

New compounds were screened to develop effective drugs against glutamate-induced toxicity. The present study assessed the effects of the novel thiazole derivative KHG21834 against glutamate-induced toxicity in human neuroblastoma SH-SY5Y cell cultures. Treatment of SH-SY5Y cells with KHG21834 significantly protected cells against glutamate-induced toxicity in a dose-dependent manner, with an optimum concentration of 50 μM.

Effects of α-lipoic acid on LPS-induced neuroinflammation and NLRP3 inflammasome activation through the regulation of BV-2 microglial cells activation.

Microglial cells are known as the main immune cells in the central nervous system, both regulating its immune response and maintaining its homeostasis. Furthermore, the antioxidant α-lipoic acid (LA) is a recognized therapeutic drug for diabetes because it can easily invade the blood-brain barrier. This study investigated the effect of α-LA on the inflammatory response in lipopolysaccharide (LPS)-treated BV-2 microglial cells.

3-(Naphthalen-2-yl(propoxy)methyl)azetidine hydrochloride attenuates MPP＋-induced cytotoxicity by regulating oxidative stress and mitochondrial dysfunction in SH-SY5Y cells.

Parkinson's disease (PD) is a common chronic neurodegenerative disease mainly caused by the death of dopaminergic neurons. However, no complete pharmacotherapeutic approaches are currently available for PD therapies. 1-methyl-4- phenylpyridinium (MPP＋)-induced SH-SY5Y neurotoxicity has been broadly utilized to create cellular models and study the mechanisms and critical aspects of PD.

Construction of Druglike 2-Amido Benzo[ d]imidazole Analogues via Desulfurative Cyclization of Thiourea Intermediate Resin on Solid-Phase.

A 2-amido benzo[ d]imidazole library has been constructed by solid-phase synthesis. The key step of this solid-phase synthesis involves the preparation of polymer-bound 2-amino benzo[ d]imidazole resin through desulfurative cyclization of thiourea resin using 2-chloro-1,3-dimethylimidazolinium chloride and N, N-diisopropylethylamine in dichloromethane (DCM), and the resin is then functionalized by acylation at the 2-amine position to afford 2-amidobenzo[ d]imidazole resin. In the case of 2-amidobenzo[ d]imidazole resin having a p-I or m-NO, the resin was further functionalized by Suzuki/Sonogashira-coupling ( p-I) and reduction to the primary amine ( m-NO) followed by acylation.

Construction of 1,3,4-Oxadiazole and 1,3,4-Thiadiazole Library with a High Level of Skeletal Diversity Based on Branching Diversity-Oriented Synthesis on Solid-Phase Supports.

An efficient solid-phase synthetic route for the construction of 1,3,4-oxadiazole and 1,3,4-thiadiazole libraries based on branching diversity-oriented synthesis (DOS) has been developed in this study. The core skeleton resins, 1,3,4-oxadiazole and 1,3,4-thiadiazole, were obtained through desulfurative and dehydrative cyclizations of thiosemicarbazide resin, respectively. Various functional groups have been introduced to the core skeleton resins, such as aryl, amine, amide, urea, thiourea, and an amino acid.

3-(Naphthalen-2-yl(propoxy)methyl)azetidine hydrochloride attenuates NLRP3 inflammasome-mediated signaling pathway in lipopolysaccharide-stimulated BV2 microglial cells.

The nucleotide-binding and oligomerization domain-like receptor containing a pyrin domain 3 (NLRP3) inflammasome is a multiprotein complex with a role in innate immune responses. NLRP3 inflammasome dysfunction is a common feature of chronic inflammatory diseases. Microglia activation is also associated with neuroinflammatory pathologies.

Synthesis of 2-Alkoxy/Thioalkoxy Benzo[d]imidazoles and 2-Thione Benzo[d]imidazoles via a Phase-Based, Chemoselective Reaction.

2-Alkoxy/thioalkoxy benzo-[d]-imidazole and 2-thione benzo-[d]-imidazole libraries were constructed in solution phase and on solid phase, respectively. The key step in this work is the phase-based chemoselective reaction of the 2-mercaptobenzo-[d]-imidazole intermediate with benzyl chloride (solution phase) and Merrifield resin (solid phase). In the solution-phase case, benzyl chloride reacted with the thiol group of 2-mercaptobenzo-[d]-imidazole, whereas in the solid-phase case, Merrifield resin was introduced at an internal amine group of benzo-[d]-imidazole.

Anti-inflammatory and anti-oxidative effects of 3-(naphthalen-2-yl(propoxy)methyl)azetidine hydrochloride on β-amyloid-induced microglial activation.

We aimed to assess the anti-inflammatory and antioxidative properties of KHG26792, a novel azetidine derivative, in amyloid β (Aβ)-treated primary microglial cells. KHG26792 attenuated the Aβ-induced production of inflammatory mediators such as IL-6, IL-1β, TNF-α, and nitric oxide. The levels of protein oxidation, lipid peroxidation, ROS, and NADHP oxidase enhanced by Aβ were also downregulated by KHG26792 treatment.

N-Adamantyl-4-Methylthiazol-2-Amine Attenuates Glutamate-Induced Oxidative Stress and Inflammation in the Brain.

In this study, we explored the possible mechanisms underlying the neuroprotective and anti-oxidative effects of N-adamantyl-4-methylthiazol-2-amine (KHG26693) against in vivo glutamate-induced toxicity in the rat cerebral cortex. Our results showed that pretreatment with KHG26693 significantly attenuated glutamate-induced elevation of lipid peroxidation, tumor necrosis factor-α, interferon gamma, IFN-γ, interleukin-1β, nitric oxide, reactive oxygen species, NADPH oxidase, caspase-3, calpain activity, and Bax. Furthermore, KHG26693 pretreatment attenuated key antioxidant parameters such as levels of superoxide dismutase, catalase, glutathione, and glutathione reductase.

Solid-Phase Parallel Synthesis of N-Substituted-2-aminothiazolo[4,5-b]pyrazine Derivatives via Tandem Reaction of Isothiocyanate Terminated Resin with o-Bromo-2-Aminopyrazines.

A novel solid-phase synthesis methodology of N-substituted-2-aminothiazolo[4,5-b]pyrazine derivatives was developed. The key step in this synthesis strategy is the tandem reaction of isothiocyanate terminated resin 2 with o-bromo-2-aminopyrazine, affording cyclized 2-aminothiazolo[4,5-b]pyrazine resin 4. To increase the diversity of our library, Suzuki coupling reaction was performed at the position C6.

Protective effect of 3-(naphthalen-2-yl(propoxy)methyl)azetidine hydrochloride on hypoxia-induced toxicity by suppressing microglial activation in BV-2 cells.

We recently reported the anti-inflammatory effects of 3-(naphthalen-2-yl(propoxy)methyl)azetidine hydrochloride (KHG26792) on the ATP-induced activation of the NFAT and MAPK pathways through the P2X7 receptor in microglia. To further investigate the underlying mechanism of KHG26792, we studied its protective effects on hypoxia-induced toxicity in microglia. The administration of KHG26792 significantly reduced the hypoxia-induced expression and activity of caspase-3 in BV-2 microglial cells.

Solid-Phase Synthesis of 1,3,4-Thiadiazole Derivatives via Desulfurative Cyclization of Thiosemicarbazide Intermediate Resin.

A 1,3,4-thiadiazole library was constructed by solid-phase organic synthesis. The key step of this solid-phase synthesis involves the preparation of polymer-bound 2-amido-5-amino-1,3,4-thiadiazole resin by the cyclization of thiosemicarbazide resin using p-TsCl as the desulfurative agent, followed by the functionalization of the resin by alkylation, acylation, alkylation/acylation, and Suzuki coupling reactions. Both the alkylation and acylation reactions chemoselectively occurred at the 2-amide position of 2-amido-5-amino-1,3,4-thiadiazole resin and the 5-amine position of 2-amido-5-amino-1,3,4-thiadiazole resin, respectively.

N-Adamantyl-4-methylthiazol-2-amine suppresses amyloid β-induced neuronal oxidative damage in cortical neurons.

Recently, we have reported that N-adamantyl-4-methylthiazol-2-amine (KHG26693) successfully reduced the production of oxidative stress in streptozotocin-induced diabetic rats and lipopolysaccharide-induced BV-2 microglial cells by increasing their antioxidant capacity. However, antioxidative effects of KHG26693 against Aβ (Aβ)-induced oxidative stress have not yet been reported. In the present study, we further investigated the antioxidative function of KHG26693 in Aβ-mediated primary cultured cortical neurons.

A Highly Efficient Diversification of 2-Amino/Amido-1,3,4-oxadiazole and 1,3,4-Thiadiazole Derivatives via Reagent-Based Cyclization of Thiosemicarbazide Intermediate on Solid-Phase.

A 2-amino/amido-1,3,4-oxadiazole and 1,3,4-thiadiazole library has been constructed on solid-phase organic synthesis. The key step on this solid-phase synthesis involves the preparation of polymer-bound 2-amino-1,3,4-oxadiazole and 1,3,4-thiadiazole core skeleton resin by cyclization of thiosemicarbazide with EDC·HCl and p-TsCl, respectively. The resulting core skeleton undergoes functionalization reaction with various electrophiles such as alkyl halides, and acid chlorides to generate N-alkylamino and N-acylamino-1,3,4-oxadiazole, and 1,3,4-thiadiazole resin, respectively.

The azetidine derivative, KHG26792 protects against ATP-induced activation of NFAT and MAPK pathways through P2X7 receptor in microglia.

Azetidine derivatives are of interest for drug development because they may be useful therapeutic agents. However, their mechanisms of action remain to be completely elucidated. Here, we have investigated the effects of 3-(naphthalen-2-yl(propoxy)methyl)azetidine hydrochloride (KHG26792) on ATP-induced activation of NFAT and MAPK through P2X7 receptor in the BV-2 mouse microglial cell line.

2-Cyclopropylimino-3-methyl-1,3-thiazoline hydrochloride alters lipopolysaccharide-induced proinflammatory cytokines and neuronal morphology in mouse fetal brain.

It is well documented that a maternal immune response to infection during pregnancy can cause neurodevelopmental damage. We demonstrate in our current study that maternally administered 2-cyclopropylimino-3-methyl-1,3-thiazoline hydrochloride (KHG26377), a novel thiazole derivative, prevents fetal malformations and neurodevelopmental deficits in offspring by blocking lipopolysaccharide (LPS)-induced inflammation. Administration of KHG26377 effectively regulated LPS-induced inflammatory markers and mediators such as soluble intercellular adhesion molecule-1, se-Selectin, macrophage chemoattractant protein-1, and cytokine-induced neutrophil chemoattractant-1 in the maternal serum.

The ABCG2 Polymorphism rs2725220 Is Associated with Hyperuricemia in the Korean Population.

Elevated serum uric acid levels are associated with a variety of adverse health outcomes, including gout, hypertension, diabetes mellitus, metabolic syndrome, and cardiovascular diseases. Several genome-wide association studies on uric acid levels have implicated the ATP-binding cassette, subfamily G, member 2 (ABCG2) gene as being possibly causal. We investigated an association between the single-nucleotide polymorphism (SNP) rs2725220 in the ABCG2 gene and uric acid levels in the Korean population.

Effects of N-adamantyl-4-methylthiazol-2-amine on hyperglycemia, hyperlipidemia and oxidative stress in streptozotocin-induced diabetic rats.

Thiazole derivatives are attractive candidates for drug development because they can be efficiently synthesized and are active against a number of diseases and conditions, including diabetes. In our present study, we investigated the anti-inflammatory and antioxidant properties of N-adamantyl-4-methylthiazol-2-amine (KHG26693), a new thiazole derivative, in a streptozotocin (STZ)-induced model of diabetes mellitus. STZ-induced diabetic rats were intraperitoneally administered KHG26693 (3mg/kg-body weight/day) for 4 weeks.

Regioselective synthesis of 2-amino-substituted 1,3,4-oxadiazole and 1,3,4-thiadiazole derivatives via reagent-based cyclization of thiosemicarbazide intermediate.

A regioselective, reagent-based method for the cyclization reaction of 2-amino-1,3,4-oxadiazole and 2-amino-1,3,4-thiadiazole core skeletons is described. The thiosemicarbazide intermediate 3 was reacted with EDC·HCl in DMSO or p-TsCl, triethylamine in N-methyl-2-pyrrolidone to give the corresponding 2-amino-1,3,4-oxadiazoles 4 and 2-amino-1,3,4-thiadiazoles 5 through regioselcective cyclization processes. The regioselectivity was affected by both R(1) and R(2) in p-TsCl mediated cyclization.

Inhibition of glutamate dehydrogenase and insulin secretion by KHG26377 does not involve ADP-ribosylation by SIRT4 or deacetylation by SIRT3.

We investigated the mechanisms involved in KHG26377 regulation of glutamate dehydrogenase (GDH) activity, focusing on the roles of SIRT4 and SIRT3. Intraperitoneal injection of mice with KHG26377 reduced GDH activity with concomitant repression of glucose-induced insulin secretion. Consistent with their known functions, SIRT4 ribosylated GDH and reduced its activity, and SIRT3 deacetylated GDH, increasing its activity.